NLRP3 modulators

ABSTRACT

This disclosure features compounds of Formula I, or a pharmaceutically acceptable salt thereof: 
                         
in which R 1 , R 2 , R 3 , and R 4  are as defined herein. These compounds are modulators of NLRP3, which are useful, e.g., for treating a condition, disease or disorder in which a decrease in NLRP3 activity (e.g., a condition, disease or disorder associated with repressed or impaired NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

This application is a 371 of International Application No.PCT/US2017/028384 filed on Apr. 19, 2017, which claims the benefit ofpriority of U.S. Provisional Application 62/324,626, filed Apr. 19, 2016and U.S. Provisional Application 62/460,519, filed Feb. 17, 2017, eachof which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which a decrease in NLRP3 activity(e.g., a condition, disease or disorder associated with repressed orimpaired NLRP3 signaling) contributes to the pathology and/or symptomsand/or progression of the condition, disease or disorder (e.g., cancer)in a subject (e.g., a human). This disclosure also features compositionsas well as other methods of using and making the same.

BACKGROUND

Nucleotide-binding oligomerization domain-like receptors (“NLRs”)include a family of intracellular receptors that detectspathogen-associated molecular patterns (“PAMPs”) and endogenousmolecules (see, e.g., P.-Y. Ting, et al., “The NLR gene family: astandard nomenclature,” Immunity, vol. 28, no. 3, pp. 285-287, 2008).

NLRPs represent a subfamily of NLRs that include a Pyrin domain and areconstituted by proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, andNLRP12. NLRPs are believed to be involved with the formation ofmultiprotein complexes termed inflammasomes (see, e.g., C. Chaput, etal., “NOD-like receptors in lung diseases,” Frontiers in Immunology,vol. 4, article 393, 2013). These complexes typically include one or twoNLR proteins, the adapter molecule apoptosis associated speck-likecontaining a CARD domain (ASC) and pro-caspase-1 F (see, e.g.,Bauernfeind and V. Hornung, “Of inflammasomes and pathogens—sensing ofmicrobes by the inflammasome,” EMBO Molecular Medicine, vol. 5, no. 6,pp. 814-826, 2013).

One such inflammasome is formed by the NLRP3 scaffold, the ASC adaptorand caspase-1 (see, e.g., J. A. Hirota, et al., “The airway epitheliumnucleotide-binding domain and leucine-rich repeat protein 3 inflammasomeis activated by urban particulate matter,” Journal of Allergy andClinical Immunology, vol. 129, no. 4, pp. 1116.e6-1125.e6, 2012), andits expression is believed to be induced by inflammatory cytokines andTLR agonists in myeloid cells and human bronchial epithelial cells (Id).The NLRP3 inflammasome is believed to mediate the caspase-1-dependentconversion of pro-IL-1β and pro-IL-18 to IL-1β and IL-18. Further, IL-1βand IL-18 have been shown to play an important role in the treatment ofvarious types of cancer (see, e.g., EMBO Mol Med. 2012 4:1276 and PLoSOne 2011 6:e24241). IL-18 has been shown to override resistance tocheckpoint inhibitors in colon cancer tumor models (see Clin. CancerRes. 2016 Jan. 11. pii: clincanres.1655.2015).

SUMMARY

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which a decrease in NLRP3 activity(e.g., a condition, disease or disorder associated with repressed orimpaired NLRP3 signaling) contributes to the pathology and/or symptomsand/or progression of the condition, disease or disorder (e.g., cancer)in a subject (e.g., a human). This disclosure also features compositionsas well as other methods of using and making the same.

An “agonist” of NLRP3 includes compounds that, at the protein level,directly bind or modify NLRP3 such that an activity of NLRP3 isincreased, e.g., by activation, stabilization, altered distribution, orotherwise.

Certain compounds described herein that agonize NLRP3 to a lesser extentthan a NLRP3 full agonist can function in assays as antagonists as wellas agonists. These compounds antagonize activation of NLRP3 by a NLRP3full agonist because they prevent the full effect of NLRP3 interaction.However, the compounds also, on their own, activate some NLRP3 activity,typically less than a corresponding amount of the NLRP3 full agonist.Such compounds may be referred to as “partial agonists of NLRP3”.

In some embodiments, the compounds described herein are agonists (e.g.full agonists) of NLRP3. In other embodiments, the compounds describedherein are partial agonists of NLRP3.

Generally, a receptor exists in an active (Ra) and an inactive (Ri)conformation. Certain compounds that affect the receptor can alter theratio of Ra to Ri (Ra/Ri). For example, a full agonist increases theratio of Ra/Ri and can cause a “maximal”, saturating effect. A partialagonist, when bound to the receptor, gives a response that is lower thanthat elicited by a full agonist (e.g., an endogenous agonist). Thus, theRa/Ri for a partial agonist is less than for a full agonist. However,the potency of a partial agonist may be greater or less than that of thefull agonist.

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof, are featured:

in which R¹, R², R³, and R⁴ can be as defined anywhere herein.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing, antagonizing) NLRP3 activity are featured that includecontacting NLRP3 with a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame). Methods include in vitro methods, e.g., contacting a sample thatincludes one or more cells comprising NLRP3 (e.g., THP-1 cells) with thechemical entity. Methods can also include in vivo methods; e.g.,administering the chemical entity to a subject (e.g., a human) having adisease in which repressed or impaired NLRP3 signaling contributes tothe pathology and/or symptoms and/or progression of the disease (e.g.,cancer, e.g., a refractory cancer).

In another aspect, methods of treating cancer are featured that includeadministering to a subject in need of such treatment an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same).

In a further aspect, methods of treatment of a disease in whichrepressed or impaired NLRP3 signaling contributes to the pathologyand/or symptoms and/or progression of the disease are featured thatinclude administering to a subject in need of such treatment aneffective amount of a chemical entity described herein (e.g., a compounddescribed generically or specifically herein or a pharmaceuticallyacceptable salt thereof or compositions containing the same).

In another aspect, methods of treatment are featured that includeadministering to a subject having a disease in which repressed orimpaired NLRP3 signaling contributes to the pathology and/or symptomsand/or progression of the disease an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In a further aspect, methods of treatment that include administering toa subject a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same), wherein the chemicalentity is administered in an amount effective to treat a disease inwhich repressed or impaired NLRP3 signaling contributes to the pathologyand/or symptoms and/or progression of the disease, thereby treating thedisease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional cancer therapies (e.g., surgery, radiotherapy, chemotherapy,toxin therapy, immunotherapy, cryotherapy or gene therapy, or acombination thereof; e.g., chemotherapy that includes administering oneor more (e.g., two, three, four, five, six, or more) additionalchemotherapeutic agents. Non-limiting examples of additionalchemotherapeutic agents is selected from an alkylating agent (e.g.,cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprineand/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or ataxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or VindesineTaxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type Itopoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, suchas irinotecan and/or topotecan; amsacrine, etoposide, etoposidephosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin,anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin,epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., alutenizing hormone releasing hormone agonist; e.g., leuprolidine,goserelin, triptorelin, histrelin, bicalutamide, flutamide and/ornilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab,Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin,Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab,Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomabtiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab,Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab,Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent;a cytokine; a thrombotic agent; a growth inhibitory agent; ananti-helminthic agent; and an immune checkpoint inhibitor that targetsan immune checkpoint receptor selected from the group consisting ofCTLA-4, PD-1, PD-L1, PD-1—PD-L1, PD-1—PD-L2, T cell immunoglobulin andmucin 3 (TIM3 or HAVCR2), Galectin 9—TIM3, Phosphatidylserine—TIM3,lymphocyte activation gene 3 protein (LAG3), MHC class II—LAG3,4-IBB-4-IBB ligand, OX40-OX40 ligand, GITR, GITR ligand—GITR, CD27,CD70-CD27, TNFRSF25, TNFRSF25-TL A, CD40L, CD40-CD40 ligand,HVEM-LIGHT-LTA, HVEM, HVEM—BTLA, HVEM—CD160, HVEM—LIGHT,HVEM-BTLA-CD160, CD80, CD80—PDL-1, PDL2—CD80, CD244, CD48—CD244, CD244,ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR familymembers, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244,CD28, CD86—CD28, CD86—CTLA, CD80—CD28, Phosphatidylserine, TIM3,Phosphatidylserine—TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, andCD155 (e.g., CTLA-4 or PD1 or PD-L1) and other immunomodulatory agents,such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10,transforming growth factor-β (TGFβ), CD39, CD73 Adenosine-CD39-CD73, andCXCR4-CXCL12.

The subject can have cancer; e.g., the subject has undergone and/or isundergoing and/or will undergo one or more cancer therapies.

Non-limiting examples of cancer include acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile ductcancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

In other embodiments, the mammal has been identified as having a canceror an infectious disease. Representative infectious diseases include,without limitation, Acinobacter infection, actinomycosis, Africansleeping sickness, acquired immunodeficiency syndrome, amebiasis,anaplasmosis, anthrax, Arcanobacterium haemolyticum infection, Argentinehemorrhagic fever, ascariasis, aspergillosis, astrovirus infection,babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterialvaginosis, Bacteroides infection, balantidiasis, Baylisascarisinfection, BK virus infection, black piedra, Blastocystic hominisinfection, blastomycosis, Bolivian hemorrhagic fever, botulism,Brazilian hemorrhagic fever, brucellosis, bubonic plaque, Burkholderiinfection, Buruli ulcer, Calicivirus infection, camptobacteriosis,candidiasis, cat-scratch disease, cellulitis, Chagas disease, chancroid,chickenpox, chikungunya, chlamydia, Chlamydophila pneumoniae infection,cholera, chromoblastomycosis, clonorchiasis, Clostridium difficileinfection, coccidioidomycosis, Colorado tick fever, common cold,Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever,crytococcosis, cryptosporidiosis, cutaneous larva migrans,cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever,Desmodesmus infection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Sträussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, a variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, staphylococcal infection, strongyloidiasis,subacute sclerosing panencephalitis, syphilis, taeniasis, tetanus, tineabarabe, tinea capitis, tinea corporis, tinea cruris, tinea manum, tineanigra, tinea pedis, tinea unguium, tinea versicolor, toxocariasis,trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis,tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticuminfection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia,West Nile fever, white piedra, Yersinia psuedotuberculosis infection,yersiniosis, yellow fever, and zygomycosis.

The chemical entity can be administered intratumorally.

The chemical entity can be administered systemically.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Each of the patents, applications, publishedapplications, and other publications that are mentioned throughout thespecification and the attached appendices are incorporated herein byreference in their entireties.

As used herein, the term “NLRP3” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous NLRP3 molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a mitochondrial uncoupling agent or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof; e.g., a compound, such as niclosamide or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof; e.g., acompound, such as a niclosamide analog, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result includes reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case is determined using any suitabletechnique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed; Rowe et al., Eds.; The PharmaceuticalPress and the American Pharmaceutical Association: 2009; Handbook ofPharmaceutical Additives, 3rd ed; Ash and Ash Eds.; Gower PublishingCompany: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed;Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt s notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described hereinform with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, acitric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof. The “treatment of cancer”,refers to one or more of the following effects: (1) inhibition, to someextent, of tumor growth, including, (i) slowing down and (ii) completegrowth arrest; (2) reduction in the number of tumor cells; (3)maintaining tumor size; (4) reduction in tumor size; (5) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of tumor cell infiltration into peripheral organs; (6) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of metastasis; (7) enhancement of anti-tumor immune response, which mayresult in (i) maintaining tumor size, (ii) reducing tumor size, (iii)slowing the growth of a tumor, (iv) reducing, slowing or preventinginvasion and/or (8) relief, to some extent, of the severity or number ofone or more symptoms associated with the disorder.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a branched or unbranched divalent alkyl(e.g., —CH₂—).

The term “alkenyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon double bonds.The alkenyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon triple bonds.The alkynyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent, and wherein the ringcomprising a monocyclic radical is aromatic and wherein at least one ofthe fused rings comprising a bicyclic or tricyclic radical is aromatice.g. tetrahydronaphthyl. Examples of aryl groups also include phenyl,naphthyl and the like.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons, so wherein the cycloalkyl group maybe optionally substituted. Preferred cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term“cycloalkylene” as used herein refers to divalent cycloalkyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent, and whereinthe ring comprising a monocyclic radical is aromatic and wherein atleast one of the fused rings comprising a bicyclic or tricyclic radicalis aromatic (but does not have to be a ring which contains a heteroatom,e.g. tetrahydroisoquinolinyl. Examples of heteroaryl groups also includepyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl,thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like. The term“heterocycloalkylene” refers to divalent heterocyclyl.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which a decrease in NLRP3 activity(e.g., a condition, disease or disorder associated with repressed orimpaired NLRP3 signaling) contributes to the pathology and/or symptomsand/or progression of the condition, disease or disorder (e.g., cancer)in a subject (e.g., a human). This disclosure also features compositionsas well as other methods of using and making the same.

Formula I Compounds

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

wherein:

R¹ is:

(i) hydrogen;

(ii) X—R⁵, wherein X is an unbranched C₂₋₆ alkylene, and R⁵ is hydrogen,—OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); —CONR^(b)R^(c), cyano, or—NR^(b)R^(c);

(iii) (C₁₋₃ alkylene)aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or

(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and wherein the heteroaryl isoptionally substituted with from 1-3 R^(d);

R² is:

(i) Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

OR

(ii) —(Y¹)_(n)—Y²—(Y³)_(p)—R⁶, wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

OR

(iii) —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is C₂₋₅ alkylene, which is optionally substituted with from        1-6 F, and    -   R⁷ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

R³ and R⁴ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo;

(iii) cyano;

(iv) CO₂R^(a);

(v) CONR^(b)R^(c);

(vi) C₁₋₄ alkyl;

(vii) C₁₋₄ haloalkyl;

(viii) C₁₋₄ alkoxy; and

(ix) C₁₋₄ haloalkoxy;

R^(a) is:

(i) H;

(ii) C₁₋₆ alkyl optionally substituted with from 1-2 substituentsindependently selected from —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano;

(iii) C₃₋₆ cycloalkyl optionally substituted with from 1-4 substituentsindependently selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, —OH,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; or

(iv) benzyl, wherein the phenyl portion is optionally substituted withfrom 1-4 substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, F, Cl, Br, —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, cyano, CO₂(C₁₋₆alkyl); —CONR^(j)R^(k), and —NR^(j)R^(k);

each occurrence of R^(b) and R^(c) is independently selected from thegroup consisting of: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄alkyl), —S(O)₁₋₂(R^(h)), —C(O)NR^(j)R^(k), —OH, and C₁₋₄ alkoxy; orR^(b) and R^(c), together with the nitrogen atom to which each isattached forms heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from the group consistingof N(R^(f)), O, and S, and wherein the heterocyclyl is optionallyfurther substituted with from 1-4 R^(g),

each occurrence of R^(d) is independently selected from the groupconsisting of:

(i) halo;

(ii) cyano;

(iii) C₁₋₄ alkyl optionally substituted with from 1-2 substituentsindependently selected from —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,—CO₂R^(a); —CONR^(b)R^(c), cyano, and —NR^(b)R^(c);

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of nitrogen, oxygen and sulfur, wherein theheterocyclyl is optionally substituted with from 1-4 independentlyselected C₁₋₄ alkyl;

(xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from 1-3 R^(m);

(xii) —(C₀₋₃ alkylene)-heteroaryl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of nitrogen, oxygen and sulfur, wherein the heteroarylis optionally substituted with from 1-3 R^(m);

(xiii) —S(O)₁₋₂(R^(h)); and

(xiv) —NR^(b)R^(c);

each occurrence of R^(e) is independently selected from the groupconsisting of: F, —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, CO₂R^(a);—OC(O)R^(h), —CONR^(b)R^(c), and —NR^(b)R^(c);

each occurrence of R^(f) is independently selected from the groupconsisting of: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl),—C(O)NR^(j)R^(k), —S(O)₁₋₂R^(h), —OH, and C₁₋₄ alkoxy;

each occurrence of R^(g) is independently selected from the groupconsisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, CO₂R^(a); —CONR^(j)R^(k), and —NR^(j)R^(k);

each occurrence of R^(h) is independently selected from the groupconsisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,phenyl optionally substituted with from 1-3 R^(m), and heteroarylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of nitrogen, oxygen andsulfur, wherein the heteroaryl is optionally substituted with from 1-3R^(m);

each occurrence of R^(j) and R^(k) is independently selected from thegroup consisting of: H and C₁₋₄ alkyl; and

each occurrence of R^(m) is independently selected from the groupconsisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, —OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, cyano, CO₂R^(a); —CONR^(j)R^(k), and —NR^(j)R^(k).

In another aspect, compounds of Formula I, or a pharmaceuticallyacceptable salt thereof are featured:

wherein:R¹ is:(i) H(ii) X—R⁵, wherein X is an unbranched C₁₋₆ alkylene, and R⁵ is hydrogen,—OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), —CONR^(b)R^(c); cyano, or—NR^(b)R^(c);(iii) (C₁₋₃ alkylene)aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and wherein the heteroaryl isoptionally substituted with from 1-3 R^(d);R² is:(i) Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;        OR        (ii) —(Y¹)^(n)—Y²—(Y³)_(p)—R^(6′), wherein:    -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from the group consisting        of nitrogen, oxygen and sulfur, wherein R^(6′) cannot be H when        Y² is C₃₋₆ cycloalkylene optionally substituted with from 1-4        R^(g);        OR        (iii) —Z¹—Z²—Z³—R⁷, wherein:    -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is C₂₋₈₅ alkylene, which is optionally substituted with from        1-6 F, and    -   R⁷ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;        R³ and R⁴ are each independently selected from the group        consisting of:        (i) hydrogen;        (ii) halo;        (iii) cyano;        (iv) CO₂R^(a);        (v) CONR^(b)R^(c);        (vi) C₁₋₄ alkyl, optionally substituted with from 1-2        substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, —CO₂R^(a); —CONR^(b)R^(c), cyano, and —NR^(b)R^(c);        (vii) C₁₋₄ haloalkyl;        (viii) C₁₋₄ alkoxy;        (ix) C₁₋₄ haloalkoxy;        (x) —(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl        is optionally substituted with from 1-4 independently selected        R^(g), wherein y is 0 or 1;        (xi) —(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from the group consisting of N(R^(f)), O, and S,        wherein the heterocyclyl is optionally substituted with from 1-4        substituents independently selected from oxo and R^(g), wherein        y is 0 or 1;        (xii) —(C₁₋₃ alkylene)_(y)-phenyl optionally substituted with        from 1-4 R^(d), wherein y is 0 or 1;        (xiii) —(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring        atoms, wherein from 1-4 ring atoms are each independently        selected from the group consisting of N, N(R^(f)), O, and S,        wherein the heteroaryl is optionally substituted with from 1-3        R^(d), wherein y is 0 or 1;        (xiv) —Y—(C₆-C₁₀ aryl) optionally substituted with from 1-4        R^(d), wherein Y is 0 or S;        (xv) —Y-heteroaryl including from 5-10 ring atoms, wherein from        1-3 ring atoms are each independently selected from the group        consisting of N, N(R^(f)), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(d), wherein Y is O or S;        (xvi) —SO₂(C₁₋₆ alkyl); and        (xvii) —NR^(b)R^(c);        R^(a) is:        (i) H;        (ii) C₁₋₆ alkyl optionally substituted with from 1-2        substituents independently selected from —OH, —NR^(j)R^(k);        —N(H)(C(═O)C₁₋₄ alkyl), —N(H)(C(═O)OC₁₋₄ alkyl), —CO₂(C₁₋₆        alkyl); —CONR^(j)R^(k), or cyano;        (iii) C₃₋₆ cycloalkyl optionally substituted with from 1-4        substituents independently selected from C₁₋₄ alkyl, C₁₋₄        haloalkyl, F, Cl, Br, —NR^(j)R^(k); —N(H)(C(═O)C₁₋₄ alkyl),        —N(H)(C(═O)OC₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl); —CONR^(j)R^(k), —OH,        C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; or        (iv) benzyl, wherein the phenyl portion is optionally        substituted with from 1-4 substituents independently selected        from C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, —OH, C₁₋₄ alkoxy,        C₁₋₄ haloalkoxy, —N(H)(C(═O)C₁₋₄ alkyl), —N(H)(C(═O)OC₁₋₄        alkyl), cyano, —CO₂(C₁₋₆ alkyl); —CONR^(j)R^(k), and        —NR^(j)R^(k);        (v) C₆₋₁₀ aryl optionally substituted with from 1-3 R^(m);        (vi) heteroaryl including from 5-10 ring atoms, wherein from 1-3        ring atoms are each independently selected from the group        consisting of nitrogen, oxygen and sulfur, wherein so the        heteroaryl is optionally substituted with from 1-3 R^(m);        each occurrence of R^(b) and R^(c) is independently selected        from the group consisting of: R^(a); —C(O)(R^(a)),        —C(O)O(R^(a)), —S(O)₁₋₂(R^(h)), and —C(O)NR^(j)R^(k); or R^(b)        and R^(c), together with the nitrogen atom to which each is        attached forms heterocyclyl including from 3-10 ring atoms,        wherein from 1-3 ring atoms are each independently selected from        the group consisting of N(R^(f)), O, and S, and wherein the        heterocyclyl is optionally further substituted with from 1-4        R^(g),        each occurrence of R^(d) is independently selected from the        group consisting of:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl optionally substituted with from 1-2        substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, —CO₂R^(a); —CONR^(b)R^(c), cyano, and —NR^(b)R^(c);        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from the group consisting of nitrogen, oxygen and        sulfur, wherein the heterocyclyl is optionally substituted with        from 1-4 independently selected C₁₋₄ alkyl;        (xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from        1-3 R^(m);        (xii) —(C₀₋₃ alkylene)-heteroaryl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from the group consisting of nitrogen, oxygen and        sulfur, wherein the heteroaryl is optionally substituted with        from 1-3 R^(m);        (xiii) —S(O)₁₋₂(R^(h)); and        (xiv) —NR^(b)R^(c);        (xv) —OH;        (xvi) —S(O)₁₋₂(NR^(b)R^(c)); and        (xvii) —C₁₋₄ thioalkoxy;        each occurrence of R^(e) is independently selected from the        group consisting of: F, —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,        CO₂R^(a); —OC(O)R^(h), —CONR^(b)R^(c), and —NR^(b)R^(c);        each occurrence of R^(f) is independently selected from the        group consisting of: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl),        —C(O)O(C₁₋₄ alkyl), —C(O)NR^(j)R^(k), —S(O)₁₋₂R^(h), —OH, and        C₁₋₄ alkoxy;        each occurrence of R^(g) is independently selected from the        group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, —OH, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, CO₂R^(a); —CONR^(j)R^(k), and        —NR^(j)R^(k);        each occurrence of R^(h) is independently selected from the        group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,        C₁₋₄ haloalkoxy, phenyl optionally substituted with from 1-3        R^(m), and heteroaryl including from 3-10 ring atoms, wherein        from 1-3 ring atoms are each independently selected from the        group consisting of nitrogen, oxygen and sulfur, wherein the        heteroaryl is optionally substituted with from 1-3 R^(m);        each occurrence of R^(j) and R^(k) is independently selected        from the group consisting of: H and C₁₋₄ alkyl;        each occurrence of R^(m) is independently selected from the        group consisting of: C₁₋₆ alkyl, C₁₋₄ haloalkyl, F, Cl, Br, —OH,        C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, cyano, CO₂R^(a); —CONR^(j)R^(k),        and —NR^(j)R^(k); and        (i) provided when Y¹ is CH₂, then R¹ cannot be (C₁₋₃        alkylene)heteroaryl including 5 ring atoms, wherein from 1-4        ring atoms are each independently selected from the group        consisting of nitrogen, oxygen and sulfur, and wherein the        heteroaryl is optionally substituted with from 1-3 R^(d).

In some embodiments, it is provided that one of R³ and R⁴ is other thanhydrogen.

Variable R²

—Y—R⁶

In some embodiments, R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur.

In some embodiments, Y is unbranched C₂₋₆ (e.g., C₂₋₄, C₂₋₃, C₂)alkylene, which is optionally substituted with from 1-4 (e.g., 1-2, 1)R^(e). In certain embodiments, Y is unbranched C₂₋₆ (e.g., C₂₋₄, C₂₋₃,C₂) alkylene, which is unsubstituted (e.g., C₂ alkylene or C₃ alkylene;e.g., C₃ alkylene).

In other embodiments, Y is branched C₃₋₆ (e.g., C₄₋₆, C₅₋₆) alkylene,which is optionally substituted with from 1-4 (e.g., 1-2, 1) R^(e). Incertain embodiments, Y has the formula, R—CH(CH₃)—R⁶, in which R is C₁₋₄alkylene. In certain embodiments, Y is a branched C₂₋₃ alkylene. Incertain embodiments, Y is a C₂ alkylene with the formula —CH(CH₃)—. Incertain embodiments, Y is a C₃ alkylene with the formula —C(CH₃)₂—.

In some embodiments, R⁶ is —OH, CO₂R^(a);—or —NR^(b)R^(c).

In certain embodiments, R⁶ is —NR^(b)R^(c).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl,—C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)),—C(O)NR^(j)R^(k), —OH, and C₁₋₄ alkoxy.

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl,—C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)), and—C(O)NR^(j)R^(k).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl, and—C(O)(C₁₋₄ alkyl).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H and C₁₋₄ alkyl.For example, R⁶ can be —NH₂, —N(H)(C₁₋₄ alkyl) (e.g., —NHCH₃) or —N(C₁₋₄alkyl)₂ (e.g., —N(CH₃)₂).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H and —C(O)(C₁₋₄alkyl). For example, one of R^(b) and R^(c) is H, and the other is—C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: C₁₋₄ alkyl and—C(O)(C₁₋₄ alkyl). For example, one of R^(b) and R^(c) is C₁₋₄ alkyl(e.g., CH₃), and the other is —C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain embodiments, R⁶ is CO₂R^(a).

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In certain embodiments, R⁶ is —OH (in certain embodiments, R² is—CH₂CH₂CH₂OH).

—(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′)

In some embodiments, R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from the group consisting        of nitrogen, oxygen and sulfur.

In some embodiments, R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from the group consisting        of nitrogen, oxygen and sulfur, wherein R^(6′) cannot be H when        Y² is C₃₋₆ cycloalkylene optionally substituted with from 1-4        R^(g);

In some embodiments, n is 0.

In some embodiments, n is 1. In certain of these embodiments, Y¹ is CH₂.

In some embodiments, Y² is C₃₋₆ (e.g., C₃₋₅, C₃₋₄) cycloalkyleneoptionally substituted with from 1-4 R^(g). In certain embodiments, p is0. In certain embodiments, p is 1; in certain of these embodiments, Y³is C₁₋₂ alkylene.

In some embodiments, Y² is heterocycloalkylene including from 3-8 (e.g.,5-8, 6-8, 7-8, 4-6, 5-6) ring atoms, wherein from 1-2 (e.g., 1) ringatoms are each independently selected from the group consisting of N,N(R^(f)), and oxygen, and wherein Y² is optionally further substitutedwith from 1-4 R^(g).

In some embodiments, Y² is heterocycloalkylene including from 3-6 (e.g.,4-6, 5-so 6) ring atoms, wherein from 1-2 (e.g., 1) ring atoms are eachindependently selected from the group consisting of N, N(R^(f)), andoxygen, and wherein Y² is optionally further substituted with from 1-4R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein from 1-2 ring atoms are eachindependently selected from the group consisting of N and N(R^(f)), andwherein Y² is optionally further substituted with from 1-4 R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein 1 ring atom is N(R^(f)), andwherein Y² is optionally further substituted with from 1-4 R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein 1 ring atom is N, and wherein Y² isoptionally further substituted with from 1-4 R^(g). In certain of theseembodiments, the ring atom N is attached to Y¹, when present, or theimidazole ring of formula (I). In other of these embodiments, the ringatom N is attached to Y³, when present, or R⁶. In certain embodiments, pis 0. In certain embodiments, p is 1; in certain of these embodiments,Y³ is C₂₋₃ alkylene. In still other embodiments, the ring atom N isattached to the imidazole ring of formula (I). In still otherembodiments, the ring atom N is attached to R⁶. In another embodiment, nis 0, p is 0, and the ring atom N is attached to R⁶.

In some —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′) embodiments, R^(6′) can be asdefined above in conjunction with variable Y. In certain embodiments,R^(6′) can be H.

—Z¹—Z²—Z³—R⁷

In some embodiments, R² is —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is unbranched or branched C₁₋₃ alkylene, which is optionally        substituted with from 1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is unbranched or branched C₂₋₅ alkylene, which is optionally        substituted with from 1-6 F, and    -   R⁷ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

In some embodiments, Z¹ is CH₂.

In some embodiments, Z² is —O—, or —S— (e.g., —O—).

In some embodiments, Z² is —N(R^(f))—. For example, Z² can be —NH—,—N(C₁₋₄ alkyl)-, or —NC(O)(C₁₋₄ alkyl)- (e.g., —NC(O)(CH₃)—).

In some embodiments, Z³ is C₂₋₃ alkylene.

In some embodiments, R⁷ is —OH, CO₂R^(a);—or —NR^(b)R^(c).

In certain embodiments, R⁷ is —NR^(b)R^(c).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl,—C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)),—C(O)NR^(j)R^(k), —OH, and C₁₋₄ alkoxy.

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl,—C(O)(C₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)), and—C(O)NR^(j)R^(k).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H, C₁₋₄ alkyl, and—C(O)(C₁₋₄ alkyl).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H and C₁₋₄ alkyl.For example, R⁶ can be —NH₂, —N(H)(C₁₋₄ alkyl) (e.g., —NHCH₃) or —N(C₁₋₄alkyl)₂ (e.g., —N(CH₃)₂).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: H and —C(O)(C₁₋₄alkyl). For example, one of R^(b) and R^(c) is H, and the other is—C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from the group consisting of: C₁₋₄ alkyl and—C(O)(C₁₋₄ alkyl). For example, one so of R^(b) and R^(c) is C₁₋₄ alkyl(e.g., CH₃), and the other is —C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain embodiments, R⁷ is CO₂R^(a).

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In certain embodiments, R⁷ is —OH.

Variables R³ and R⁴

In some embodiments, R³ and R⁴ are each independently selected from thegroup consisting of:

(i) hydrogen;

(ii) halo;

(iii) cyano;

(iv) CO₂R^(a); and

(v) CONR^(b)R^(c).

In certain embodiments, R³ and R⁴ are each independently selected fromthe group consisting of:

(i) hydrogen;

(ii) halo; and

(iv) CO₂R^(a).

In some embodiments, one of R³ and R⁴ is hydrogen, and the other is asubstituent other than hydrogen.

In certain embodiments, one of R³ and R⁴ is hydrogen, and the other ishalo or CO₂R^(a).

In certain embodiments, one of R³ and R⁴ is hydrogen, and the other ishalo (e.g., Br).

In certain embodiments, one of R³ and R⁴ is hydrogen, and the other isCO₂R^(a).

In certain of these embodiments, R^(a) is C₁₋₄ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₄ alkyl(e.g., CH₃ or CH₂CH₃).

In some embodiments, R³ is a substituent other than hydrogen, and R⁴ ishydrogen.

In certain embodiments, R³ is halo or CO₂R^(a), and R⁴ is hydrogen.

In certain embodiments, R³ is halo (e.g., Br), and R⁴ is hydrogen.

In certain embodiments, R³ is CO₂R^(a), and R⁴ is hydrogen.

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In some embodiments, R³ is hydrogen, and R⁴ is hydrogen.

In some embodiments, each of R³ and R⁴ is independently selected fromthe group consisting of:

(i) H;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding 5 ring atoms, wherein from 1 ring atom is independentlyselected from the group consisting of O and S (e.g., S), wherein theheteroaryl is optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is furyl or thienyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is thienyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₁₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

Variable R¹

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is X—R⁵, wherein X is unbranched chain C₄alkylene, and R⁵ is hydrogen, —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy,CO₂R^(a); —CONR^(b)R^(c), cyano, or —NR^(b)R^(c).

In some embodiments, X is unbranched chain C₂₋₄ alkylene. In someembodiments, X is unbranched chain C₅₋₆ alkylene.

In some embodiments, R⁵ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a);or —NR^(b)R^(c).

In certain embodiments, R⁵ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, orCO₂R^(a).

In certain embodiments, R⁵ is C₁₋₄ alkoxy or —C₁₋₄ haloalkoxy (e.g.,C₁₋₄ alkoxy, e.g., OCH₃).

In certain embodiments, R⁵ is CO₂R^(a).

In some embodiments, R⁵ is H. In certain of these embodiments, R¹ isunsubstituted C₁₋₂ alkyl (e.g., CH₃).

In certain of these embodiments, R is C₁₋₆ alkyl optionally substitutedwith —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₃alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In some embodiments, R¹ is:

(iii) (C₁₋₃ alkylene)aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or

(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and wherein the heteroaryl isoptionally substituted with from 1-3 R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)aryl, wherein the aryl isoptionally substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis optionally substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)aryl, wherein the aryl issubstituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis substituted with 1 R^(d).

In certain of these embodiments, R^(d), or at least one R^(d) is C₁₋₄(e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁) alkyl optionally substituted with from 1-2substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, —CO₂R^(a); —CONR^(b)R^(c), cyano, and —NR^(b)R^(c).

In certain of these embodiments, R^(d), or at least one R^(d) is C₁₋₆(e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁) alkyl substituted with from 1-2substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, —CO₂R^(a); —CONR^(b)R^(c), cyano, and —NR^(b)R^(c). By wayof example, R^(d) can be —CH₂NR^(b)R^(c), e.g., —CH₂NH₂.

Non-Limiting Combinations

[1] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur; and

R¹ is hydrogen.

In some of these embodiments, each of R³ and R⁴ is independentlyselected from the group consisting of:

(i) H;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

[2] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

R¹ is hydrogen; and

R³ and R⁴ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo; and

(iv) CO₂R^(a).

In certain of these embodiments, one of R³ and R⁴ is other thanhydrogen.

[3] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is CO₂ alkylene, which is optionally substituted with from 1-4        R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur; and

R¹ is X—R⁵, wherein X is unbranched chain C₂₋₆ alkylene, and R⁵ ishydrogen, —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); —CONR^(b)R^(c),cyano, or —NR^(b)R^(c).

In some embodiments, each of R³ and R⁴ is independently selected fromthe group consisting of:

(i) H;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

[4] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

R¹ is X—R⁵, wherein X is unbranched chain C₂₋₆ alkylene, and R⁵ ishydrogen, —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); —CONR^(b)R^(c),cyano, or —NR^(b)R^(c); and

R³ and R⁴ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo; and

(iv) CO₂R^(a).

In certain of these embodiments, one of R³ and R⁴ is other thanhydrogen.

[5] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur; and

R¹ is:

(iii) (C₁₋₃ alkylene)aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or

(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and wherein the heteroaryl isoptionally substituted with from 1-3 R^(d).

In some embodiments, each of R³ and R⁴ is independently selected fromthe group consisting of:

(i) H;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

[6] In some embodiments:

R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from the group consisting of        nitrogen, oxygen and sulfur;

R¹ is:

(iii) (C₁₋₃ alkylene)aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or

(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and wherein the heteroaryl isoptionally substituted with from 1-3 R^(d). and

R³ and R⁴ are each independently selected from the group consisting of:

(i) hydrogen;

(ii) halo; and

(iv) CO₂R^(a).

In certain of these embodiments, one of R³ and R⁴ is other thanhydrogen.

[7] In some embodiments:

R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from the group consisting        of nitrogen, oxygen and sulfur;

and R¹ is hydrogen.

[8] In some embodiments:

R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from the group consisting of N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from the group consisting        of nitrogen, oxygen and sulfur, wherein R^(6′) cannot be H when        Y² is C₃₋₆ cycloalkylene optionally substituted with from 1-4        R^(g);

and R¹ is hydrogen or unsubstituted C₁₋₂ alkyl (e.g., CH₃).

In some embodiments of combination [7] and [8], each of R³ and R⁴ isindependently selected from the group consisting of:

(i) H;

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(f);

(vii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are each independently selected from thegroup consisting of N(R^(e)), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(f);

(viii) —(C₀₋₃ alkylene)-C₆₋₁₀ aryl optionally substituted with from 1-4R^(g);

(ix) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from the groupconsisting of N, N(R^(e)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(g); and

(xiv) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from the group consisting ofN, N(R^(e)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(g);and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline,

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N, N(R^(e)), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from the group consisting of N and N(R^(e)),wherein the heteroaryl is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding 5 ring atoms, wherein from 1 ring atom is independentlyselected from the group consisting of O and S (e.g., S), wherein theheteroaryl is optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(g);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(g); and the other (e.g., R⁴⁾ isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is furyl or thienyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is thienyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-C₆₋₁₀ aryl, wherein the aryl is optionally substituted withfrom 1-3 R^(g); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₀₋₃alkylene)-heterocyclyl including from 3-10 ring atoms, wherein from 1-3ring atoms are each independently selected from the group consisting ofN(R^(e)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(f); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from the group consisting of N(R^(e)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(f) (e.g., oxo), and the other (e.g., R⁴) is H.

Embodiments of any one of combinations [1]-[8] can include one or moreof the following features.

Y can be unbranched C₂₋₆ (e.g., C₂₋₄, C₂₋₃, C₂) alkylene, which isoptionally substituted with from 1-4 (e.g., 1-2, 1) R^(e). In certainembodiments, Y is unbranched C₂₋₆ (e.g., C₂₋₄, C₂₋₃, C₂) alkylene, whichis unsubstituted (e.g., C₂ alkylene or C₃ alkylene; e.g., C₃ alkylene).

R⁶ can be —OH, CO₂R^(a);—or —NR^(b)R^(c).

R⁶ can be —NR^(b)R^(c).

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄alkyl), —S(O)₁₋₂(R^(h)), —C(O)NR^(j)R^(k), —OH, and C₁₋₄ alkoxy.

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄alkyl), —S(O)₁₋₂(R^(b)), and —C(O)NR^(j)R^(k).

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: H and C₁₋₄ alkyl. For example, R⁶ can be —NH₂,—N(H)(C₁₋₄ alkyl) (e.g., —NHCH₃) or —N(C₁₋₄ alkyl)₂ (e.g., —N(CH₃)₂).

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: H and —C(O)(C₁₋₄ alkyl). For example, one ofR^(b) and R^(c) is H, and the other is —C(O)(C₁₋₄ alkyl) (e.g.,—C(O)(CH₃).

Each occurrence of R^(b) and R^(c) can be independently selected fromthe group consisting of: C₁₋₄ alkyl and —C(O)(C₁₋₄ alkyl). For example,one of R^(b) and R^(c) is C₁₋₄ alkyl (e.g., CH₃), and the other is—C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

R⁶ can be CO₂R^(a). R^(a) can be C₁₋₆ alkyl optionally substituted with—OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₃ alkyl), orcyano; e.g., R^(a) can be unsubstituted C₁₋₆ alkyl (e.g., CH₃ orCH₂CH₃).

R⁶ can be —OH (in certain embodiments, R² is —CH₂CH₂CH₂OH).

X can be unbranched chain C₂₋₄ alkylene. In some embodiments, X isunbranched chain C₅₋₆ alkylene.

R⁵ can be —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); or —NR^(b)R^(c).

R⁵ can be —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, or CO₂R^(a).

R⁵ can be C₁₋₄ alkoxy or —C₁₋₄ haloalkoxy (e.g., C₁₋₄ alkoxy, e.g.,OCH₃).

R⁵ can be CO₂R^(a). R can be C₁₋₆ alkyl optionally substituted with —OH,—NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₃ alkyl), orcyano; e.g., R^(a) can be unsubstituted C₁₋₆ alkyl (e.g., CH₃ orCH₂CH₃).

R⁵ can be H; e.g., R¹ can be unsubstituted C₁₋₂ alkyl (e.g., CH₃).

R¹ can be (C₁₋₃ alkylene)aryl, wherein the aryl is optionallysubstituted with from 1-3 (e.g., 2, 1) R^(d).

R¹ can be (C₁₋₃ alkylene)phenyl, wherein the phenyl is optionallysubstituted with from 1-3 (e.g., 2, 1) R^(d).

R¹ can be (C₁₋₃ alkylene)aryl, wherein the aryl is substituted with from1-3 (e.g., 2, 1) R^(d).

R¹ can be (C₁₋₃ alkylene)phenyl, wherein the phenyl is substituted withfrom 1-3 (e.g., 2, 1) R^(d).

R¹ can be (C₁₋₃ alkylene)phenyl, wherein the phenyl is substituted with1 R^(d).

R^(d), or at least one R^(d) can be C₁₋₆ (e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁)alkyl optionally substituted with from 1-2 substituents independentlyselected from —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —CO₂R^(a);—CONR^(b)R^(c), cyano, and —NR^(b)R^(c).

R^(d), or at least one R^(d) can be C₁₋₆ (e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁)alkyl substituted with from 1-2 substituents independently selected from—OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —CO₂R^(a); —CONR^(b)R^(c), cyano, and—NR^(b)R^(c). By way of example, R^(d) can be —CH₂NR^(b)R^(c), e.g.,—CH₂NH₂.

One of R³ and R⁴ (e.g., R³) can be hydrogen, and the other (e.g., R³)can be a substituent other than hydrogen.

One of R³ and R⁴ (e.g., R³) can be hydrogen, and the other (e.g., R³)can be halo or CO₂R^(a).

One of R³ and R⁴ (e.g., R³) can be hydrogen, and the other (e.g., R³)can be halo (e.g., Br).

One of R³ and R⁴ (e.g., R³) can be hydrogen, and the other (e.g., R³)can be CO₂R^(a). R^(a) can be C₁₋₆ alkyl optionally substituted with—OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₃ alkyl), orcyano; e.g., R^(a) can be unsubstituted C₁₋₆ alkyl (e.g., CH₃ orCH₂CH₃).

R³ can be hydrogen, and R³ can be hydrogen.

In some embodiments, the compound of Formula I is a compound selectedfrom the group consisting of compounds in Table 1 below. The biologicalassays used to test the compounds is discussed in the examples section.A blank table cell indicates a lack of data of the type specified in thecell's corresponding column. Key to activity ranges: A=≤1 μM; B=>1 μM,≤20 μM; C=>20 μM, ≤100 μM; D=>10 μM.

TABLE 1 hNLRP3 Agonist TLR7 TLR8 EC₅₀ EC₅₀ EC₅₀ LCMS Compound Structure(μM) (μM) (μM) [M + H]+ 101

C C C 243.0 102

103

104

105

106

and pharmaceutically acceptable salts thereof.

In some embodiments, the compound of Formula I is a compound selectedfrom the group consisting of compounds in Table 2 below. The biologicalassays used to test the compounds is discussed in the examples section.A blank table cell indicates a lack of data of the type specified in thecell's corresponding column. Key to activity ranges: A=≤1 μM; B=>1 μM,≤20 μM; C=>20 μM, ≤100 μM; D=>100 μM.

TABLE 2 hNLRP3 Agonist TLR7 TLR8 EC₅₀ EC₅₀ EC₅₀ LCMS Structure Compound(μM) (μM) (μM) [M + H]+

107 A D D 323.2

108 A D D 323.2

109 A 376.2

110 B D D 460.2

111 B D C 257.1

112 B D D 376.0

113 B D D 323.2

114 B D D 412.1

115 B D D 327.3

116 B 363.3

117 B D D 314.9

118 B D D 341.0

119 B D D 285.1

120 B D D 313.9

121 B D D 301.1

122 B D D 363.2

123 B D D 434.2

124 B D D 273.1

125 B D D 361.2

126 B D D 311.0

127 C C D 311.0

128 C D C 275.1

129 C D D 241.1

130 C D D 257.1

131 C D C 362.0

132 C D D 255.1

133 C D D 255.1

134 C D D 283.3

135 C D D 283.2

136 C D D 279.1

137 C D D 254.9

138 C D D 282.0

139 C D D 282.0

141 B D D 421.1

142 B D D 408.9

144 409.2

145 A D D 319.1

146 C D D 410.2

147 B D D 320.1

148 C D D 410.2

149 B D D 320.1

150 D D D 427.2

151 B D D 337.2

152 C D D 441.2

153 B D D 351.2

154 B D D 425.2

155 B D D 335.1

156 D D D 364.2

157 D D D 428.2

158 B D D 338.1

159 B C D 285.2

160 A C D 285.2

161 A D D 311.2

162 B C C 271.1

163 C D D 335.1

164 D D D 323.1

165 C C C 277.1

166 D D D 312.2

167 D D D 326.2

168 D D D 328.2

169 B D D

170 D D D 335.1

171 D D D 350.1

172 D D D 334.1

173 D D D 366.1

174 C D D 325.2

175 D D D 350.1

176 D D D 336.1

177 D D D 369.1

178 A D C 309.1

179 D D D 309.1

180 D D D 362.1

181 B D D 323.1

182 D D D 359.1

183 C D D 326.1

184 D D D 326.1

185 A D D 320.1

186 A D D 325.1

187 A D D 325.1

188 C D D 321.1

189 A D D 309.1

190 C D D 323.1

191 D D D 370.1

192 D D D 370.1

193 C D D 323.1

194 C C D 337.2

195 D D D 310.1

196 D D D 327.2

197 D D 312.2

198 D D 326.2

199 D D D 333.2

200 D D D 353.1

201 D D D 349.1

202 D D D 344.1

203 D D D 337.1

204 D D D 353.1

205 C D D 333.2

206 D D D 349.1

207 D D D 344.1

208 D D D 337.1

209 D D D 353.1

210 D D D 333.2

211 D D D 349.1

212 D D C 337.1

213 D B D 334.1

214 D C D 334.1

215 D C C 354.1

218 A D D 434.3

219 A D D 444.3

220 B D D 488.2

221 B D D 445.3

222 B D D 344.3

223 B D D 412.1

224 C D D 268.2

225 B D D 446.1

226 C D D 388.1

227 C D D 551.3

228 C D D 282.1

229 C D D 348.1

230 B D D 446.1

231 B 366.0

232 B D D 376.2

233 A D D 334.3

234

235

236

237

238 B D D 336.3

239 B D D 336.1

240 B D D

241 B D D

242 B D D

243 B 415.2

246 B D D 350.3

247 B D D 440.1

249 B D D 426.4

251 B D D 336.1

252 B D D 556.6

253 B D D 378.4

and pharmaceutically acceptable salts thereof.

Pharmaceutical compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., agonizes or partially agonizes) NLRP3, or a pharmaceuticallyacceptable salt, and/or hydrate, and/or cocrystal, and/or drugcombination thereof) is administered as a pharmaceutical compositionthat includes the chemical entity and one or more pharmaceuticallyacceptable excipients, and optionally one or more additional therapeuticagents as described herein.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracisternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral). Incertain embodiments, a preferred route of administration is systemic.

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788-795.

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms.).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which a decrease or increase in NLRP3 activity(e.g., a decrease, e.g., repressed or impaired NLRP3 signaling)contributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) are provided.

Indications

In any of the methods described herein, the subject can have a cancer.In some examples of any of the methods described herein, the mammal hasbeen identified as having a cancer, or has been diagnosed as having acancer.

Non-limiting examples of cancer include: acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile ductcancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

Methods for diagnosing a subject as having a cancer or identifying amammal as having a cancer are well known in the art. For example, amedical professional (e.g., a physician, a physician's assistant, or atechnician) can diagnose cancer in a mammal by observing one or moresymptoms of cancer in a mammal. Non-limiting examples of symptoms ofcancer include: fatigue, lump or area of thickening felt under the skin,weight change, jaundice, darkening or redness of the skin, sores thatwon't heal, changes to existing moles, changes in bowel or bladderhabits, persistent cough or trouble breathing, difficulty swallowing,hoarseness, persistent indigestion or discomfort after eating,persistent, unexplained muscle or joint pain, persistent, unexplainedfevers or night sweats, and unexplained bleeding or bruising. Methods ofdiagnosing a subject as having a cancer or identifying a subject ashaving a cancer can further include performing one or more diagnostictests (e.g., performing one or more diagnostic tests on a biopsy or ablood sample).

In some examples of any of the methods described herein, a subject canbe a subject having a cancer, a subject diagnosed as having a cancer, ora subject identified as having a cancer that has been unresponsive to apreviously administered treatment for cancer. Diagnostic tests fordiagnosing a subject as having a cancer or identifying a mammal ashaving a cancer are known in the art.

In any of the methods described herein, the subject can have aninfectious disease. In some examples of any of the methods describedherein, the subject has been identified as having an infectious disease,or has been diagnosed as having an infectious disease. For example, aninfectious disease can be caused by a bacterium, virus, fungus,parasite, or a mycobacterium.

Non-limiting examples of infectious disease include: Acinobacterinfection, actinomycosis, African sleeping sickness, acquiredimmunodeficiency syndrome, amebiasis, anaplasmosis, anthrax,Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever,ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacilluscereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroidesinfection, balantidiasis, Baylisascaris infection, BK virus infection,black piedra, Blastocystic hominis infection, blastomycosis, Bolivianhemorrhagic fever, botulism, Brazilian hemorrhagic fever, brucellosis,bubonic plaque, Burkholderi infection, Buruli ulcer, Calicivirusinfection, camptobacteriosis, candidiasis, cat-scratch disease,cellulitis, Chagas disease, chancroid, chickenpox, chikungunya,chlamydia, Chlamydophila pneumoniae infection, cholera,chromoblastomycosis, clonorchiasis, Clostridium difficile infection,coccidioidomycosis, Colorado tick fever, common cold, Creutzfeldt-Jakobdisease, Crimean-Congo hemorrhagic fever, crytococcosis,cryptosporidiosis, cutaneous larva migrans, cyclosporiasis,cysticercosis, cytomegalovirus infection, dengue fever, Desmodesmusinfection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Sträussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, staphylococcal infection, strongyloidiasis,subacute sclerosing panencephalitis, syphilis, taeniasis, tetanus, tineabarabe, tinea capitis, tinea corporis, tinea cruris, tinea manum, tineanigra, tinea pedis, tinea unguium, tinea versicolor, toxocariasis,trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichuriasis,tuberculosis, tularemia, typhoid fever, Ureaplasma urealyticuminfection, valley fever, Venezuelan hemorrhagic fever, viral pneumonia,West Nile fever, white piedra, Yersinia psuedotuberculosis infection,yersiniosis, yellow fever, and zygomycosis.

Methods for diagnosing a subject as having an infectious disease, oridentifying a subject as having an infectious disease are well known inthe art. For example, a medical professional (e.g., a physician, aphysician's assistant, or a technician) can diagnose infectious diseasein a subject by observing one or more symptoms of infectious disease ina subject. Non-limiting examples of symptoms of infectious diseaseinclude: fever, diarrhea, fatigue, and muscle aches. Methods ofdiagnosing a mammal as having an infectious disease or identifying asubject as having an infectious disease can further include performingone or more diagnostic tests (e.g., performing one or more diagnostictests on a biopsy or a blood sample). Diagnostic tests for diagnosing asubject as having an infectious disease or identifying a subject ashaving an infectious disease are known in the art.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the methods described herein can further includeadministering one or more additional cancer therapies.

The one or more additional cancer therapies can include, withoutlimitation, surgery, radiotherapy, chemotherapy, toxin therapy,immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine,hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well ascombinations thereof. Immunotherapy, including, without limitation,adoptive cell therapy, the derivation of stem cells and/or dendriticcells, blood transfusions, lavages, and/or other treatments, including,without limitation, freezing a tumor.

In some embodiments, the one or more additional cancer therapies ischemotherapy, which can include administering one or more additionalchemotherapeutic agents.

In certain embodiments, the additional chemotherapeutic agent is animmunomodulatory moiety, e.g., an immune checkpoint inhibitor. Incertain of these embodiments, the immune checkpoint inhibitor targets animmune checkpoint receptor selected from the group consisting of CTLA-4,PD-1, PD-L1, PD-1—PD-L1, PD-1—PD-L2, T cell immunoglobulin and mucin 3(TIM3 or HAVCR2), Galectin 9—TIM3, Phosphatidylserine—TIM3, lymphocyteactivation gene 3 protein (LAG3), MHC class II—LAG3, 4-1BB-4-IBB ligand,OX40-OX40 ligand, GITR, GITR ligand—GITR, CD27, CD70-CD27, TNFRSF25,TNFRSF25-TL1A, CD40L, CD4-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM—BTLA,HVEM—CD160, HVEM—LIGHT, HVEM-BTLA-CD160, CD80, CD80—PDL-1, PDL2—CD80,CD244, CD48—CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA,TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family,TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICAand MICB, CD244, CD28, CD86—CD28, CD86—CTLA, CD80—CD28,Phosphatidylserine, TIM3, Phosphatidylserine—TIM3, SIRPA-CD47, VEGF,Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1) andother immunomodulatory agents, such as interleukin-2 (IL-2), indoleamine2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), CD39,CD73 Adenosine-CD39-CD73, and CXCR4-CXCL12. See, e.g., Postow, M. J.Clin. Oncol. 2015, 33, 1.

In certain of these embodiments, the immune checkpoint inhibitor isselected from the group consisting of: Urelumab, PF-05082566, MEDI6469,TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1),Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab(PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201,Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab,CC-90002, Bevacizumab, and MNRP1685A, and MGA271.

In certain embodiments, the additional chemotherapeutic agent is a STINGagonist. For example, the STING agonist can include cyclicdi-nucleotides, such as cAMP, cGMP, and cGAMP as well as modified cyclicdi-nucleotides that include one or more of the following modificationfeatures (2′-O/3′-O linkage, phosphorothioate linkage, adenine and/orguanine analogue, 2′-OH modification (e.g., —OCH₃ or replacement, e.g.,—F or N₃). See, e.g., WO 2014/189805.

In certain embodiments, the additional chemotherapeutic agent is analkylating agent. Alkylating agents are so named because of theirability to alkylate many nucleophilic functional groups under conditionspresent in cells, including, but not limited to cancer cells. In afurther embodiment, an alkylating agent includes, but is not limited to,Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents canfunction by impairing cell function by forming covalent bonds with theamino, carboxyl, sulfhydryl, and phosphate groups in biologicallyimportant molecules or they can work by modifying a cell's DNA. In afurther embodiment an alkylating agent is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is ananti-metabolite. Anti-metabolites masquerade as purines or pyrimidines,the building-blocks of DNA and in general, prevent these substances frombecoming incorporated in to DNA during the “S” phase (of the cellcycle), stopping normal development and division. Anti-metabolites canalso affect RNA synthesis. In an embodiment, an antimetabolite includes,but is not limited to azathioprine and/or mercaptopurine. In a furtherembodiment an anti-metabolite is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is a plantalkaloid and/or terpenoid. These alkaloids are derived from plants andblock cell division by, in general, preventing microtubule function. Inan embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, apodophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind tospecific sites on tubulin, inhibiting the assembly of tubulin intomicrotubules, generally during the M phase of the cell cycle. In anembodiment, a vinca alkaloid is derived, without limitation, from theMadagascar periwinkle, Catharanthus roseus (formerly known as Vincarosea). In an embodiment, a vinca alkaloid includes, without limitation,Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In anembodiment, a taxane includes, but is not limited, to Taxol, Paclitaxeland/or Docetaxel. In a further embodiment a plant alkaloid or terpernoidis a synthetic, semisynthetic or derivative. In a further embodiment, apodophyllotoxin is, without limitation, an etoposide and/or teniposide.In an embodiment, a taxane is, without limitation, docetaxel and/orortataxel. In an embodiment, a cancer therapeutic is a topoisomerase.Topoisomerases are essential enzymes that maintain the topology of DNA.Inhibition of type I or type II topoisomerases interferes with bothtranscription and replication of DNA by upsetting proper DNAsupercoiling. In a further embodiment, a topoisomerase is, withoutlimitation, a type I topoisomerase inhibitor or a type II topoisomeraseinhibitor. In an embodiment a type I topoisomerase inhibitor is, withoutlimitation, a camptothecin. In another embodiment, a camptothecin is,without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type IItopoisomerase inhibitor is, without limitation, epipodophyllotoxin. In afurther embodiment an epipodophyllotoxin is, without limitation, anamsacrine, etoposid, etoposide phosphate and/or teniposide. In a furtherembodiment a topoisomerase is a synthetic, semisynthetic or derivative,including those found in nature such as, without limitation,epipodophyllotoxins, substances naturally occurring in the root ofAmerican Mayapple (Podophyllum peltatum).

In certain embodiments, the additional chemotherapeutic agent is astilbenoid. In a further embodiment, a stilbenoid includes, but is notlimited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene,Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C,Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, HemsleyanolD, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid andDiptoindonesin A. In a further embodiment a stilbenoid is a synthetic,semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is acytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is,without limitation, an actinomycin, an anthracenedione, ananthracycline, thalidomide, dichloroacetic acid, nicotinic acid,2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is,without limitation, actinomycin D, bacitracin, colistin (polymyxin E)and/or polymyxin B. In another embodiment, an antracenedione is, withoutlimitation, mitoxantrone and/or pixantrone. In a further embodiment, ananthracycline is, without limitation, bleomycin, doxorubicin(Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin,mitomycin, plicamycin and/or valrubicin. In a further embodiment acytotoxic antibiotic is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent isselected from endostatin, angiogenin, angiostatin, chemokines,angioarrestin, angiostatin (plasminogen fragment), basement-membranecollagen-derived anti-angiogenic factors (tumstatin, canstatin, orarrestin), anti-angiogenic antithrombin III, signal transductioninhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment,fibronectin fragment, gro-beta, heparinases, heparin hexasaccharidefragment, human chorionic gonadotropin (hCG), interferonalpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12,kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs),2-methoxyestradiol, placental ribonuclease inhibitor, plasminogenactivator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment,proliferin-related protein (PRP), various retinoids,tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growthfactor-beta (TGF-β), vasculostatin, vasostatin (calreticulin fragment)and the like.

In certain embodiments, the additional chemotherapeutic agent isselected from abiraterone acetate, altretamine, anhydrovinblastine,auristatin, bexarotene, bicalutamide, BMS 184476,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,bleomycin,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide,cachectin, cemadotin, chlorambucil, cyclophosphamide,3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol,doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin,cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC),dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin(adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide,hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine,lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard),melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin,mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel,prednimustine, procarbazine, RPR109881, stramustine phosphate,tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine,vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent isplatinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, azathioprine, mercaptopurine,vincristine, vinblastine, vinorelbine, vindesine, etoposide andteniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine,etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin,methotrexate, gemcitabine, taxane, leucovorin, mitomycin C,tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide anddoxorubicin. Additional agents include inhibitors of mTOR (mammaliantarget of rapamycin), including but not limited to rapamycin,everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can beselected from those delineated in U.S. Pat. No. 7,927,613, which isincorporated herein by reference in its entirety.

In yet another embodiment, the methods can further include administeringone or both of: (i) one or more anti-fungal agents (e.g., selected fromthe group of bifonazole, butoconazole, clotrimazole, econazole,ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole,sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole,epoziconazole, fluconazole, isavuconazole, itraconazole, posaconazole,propiconazole, ravusconazole, terconazole, voriconazole, abafungin,amorolfin, butenafine, naftifine, terbinafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine,5-fluorocytosine, griseofulvin, haloprogin, tolnaflate, undecylenicacid, and balsam of peru) and (ii) one or more antibiotics (e.g.,selected from the group of amikacin, gentamicin, kanamycin, neomycin,netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin,geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem,imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin,telavancin, dalbavancin, oritavancin, clindamycin, lincomycin,daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin,roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam,furazolidone, nitrofurantoin, linezolid, posizolid, radezolid,torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,penicillin G, temocillin, ticarcillin, amoxicillin, calvulanate,ampicillin, subbactam, piperacillin, tazobactam, ticarcillin,clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin,gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin,nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine,silver sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfanilimide,sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole,sulfonamideochrysoidine, demeclocycline, minocycline, oytetracycline,tetracycline, clofazimine, dapsone, dapreomycin, cycloserine,ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin,rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin,fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin,dalopristin, thiamphenicol, tigecycyline, tinidazole, trimethoprim, andteixobactin).

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity.

By way of example, the second therapeutic agent or regimen and thechemical entity are provided to the subject simultaneously in the samedosage form. As another example, the second therapeutic agent or regimenand the chemical entity are provided to the subject concurrently inseparate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of suchtreatment (e.g., by way of biopsy, endoscopy, or other conventionalmethod known in the art). In certain embodiments, the NLRP3 protein canserve as a biomarker for certain types of cancer.

In some embodiments, the chemical entities, methods, and compositionsdescribed herein can be administered to certain treatment-resistantpatient populations (e.g., patients resistant to checkpoint inhibitors).

EXAMPLES

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. For example, the compounds described hereincan be synthesized, e.g., using one or more of the methods describedherein and/or using methods described in, e.g., US 2015/0056224, thecontents of each of which are hereby incorporated by reference in theirentirety. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and R G M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fiesers Reagents for OrganicSynthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof. The starting materials used inpreparing the compounds of the invention are known, made by knownmethods, or are commercially available. The skilled artisan will alsorecognize that conditions and reagents described herein that can beinterchanged with alternative art-recognized equivalents. For example,in many reactions, triethylamine can be interchanged with other bases,such as non-nucleophilic bases (e.g. diisopropylamine,1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, ortetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical methods thatcan be used to characterize the compounds described herein, including,for example, ¹H NMR, heteronuclear NMR, mass spectrometry, liquidchromatography, and infrared spectroscopy. The foregoing list is asubset of characterization methods available to a skilled artisan and isnot intended to be limiting.

To further illustrate the foregoing, the following non-limiting,exemplary synthetic schemes are included. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, provided with the present disclosure, and skill in theart is able to prepare and use the invention without exhaustiveexamples.

The following abbreviations have the indicated meanings:

-   -   ACN=acetonitrile    -   CH₂Cl₂=dichloromethane    -   CH₃ReO₃=methyltrioxorhenium    -   d=doublet    -   DCM=dichloromethane    -   DIEA=N,N-diethylisopropylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   ES=electrospray ionization    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   equiv=equivalents    -   g=grams    -   h=hours    -   HCl=hydrogen chloride (usually as a solution)    -   H₂O=water    -   H₂O₂=hydrogen peroxide    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HPLC=high-performance liquid chromatography    -   K₂CO₃=potassium carbonate    -   LC/MS=liquid chromatography mass spectrometer    -   LiBH₄=lithium borohydride    -   m=multiplet    -   M=molar    -   m-CPBA=meta-chloroperoxybenzoic acid    -   mg=milligram(s)    -   MeOH=methanol    -   MHz=megahertz    -   mL=milliliter(s)    -   mmol=millimole(s)    -   NaHCO₃=sodium hydrogen carbonate    -   Na₂CO₃=sodium carbonate    -   NaOH=sodium hydroxide    -   Na₂SO₄=sodium sulfate    -   NEt₃=trimethylamine    -   NH₄OH or NH₃H₂O=ammonium hydroxide    -   NH₄HCO₃=ammonium hydrogen carbonate    -   nm=nanometer    -   PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium (II) dichloride    -   Pd(dppf)Cl₂=1,1′-Bis(diphenylphosphino)ferrocene    -   PMB=para-methoxybenzyl    -   POCl₃=phosphorous oxychloride    -   ppm=parts per million    -   s=singlet    -   t=triplet    -   TFA=trifluoroacetic acid    -   TLC=thin layer chromatography    -   TsCl=para-toluenesulfonyl chloride    -   ° C.=degrees Celsius    -   μmol=micromolar

Schemes 1 and 2 show examples of methods of preparation of compoundsdisclosed herein:

Representative Preparative Examples Preparative Example 1—Compound 101

1. Synthesis of Methyl 3-[(3-aminoquinolin-4-yl)carbamoyl]propanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 4-methoxy-4-oxobutanoicacid (1.98 g, 15.00 mmol, 1.00 equiv), DIEA (2.9 g, 22.50 mmol, 1.50equiv) and HATU (8.55 g, 22.50 mmol, 1.50 equiv) inN,N-dimethylformamide (50 mL). The resulting solution was stirred for1.5 h at 0° C. in a water and ice bath. Then to the mixture was added asolution of quinoline-3,4-diamine (2.385 g, 15.00 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL). The resulting solution was allowed to stirfor an additional 4 h at room temperature. The resulting solution wasdiluted with 100 mL of DCM. The solids were collected by filtration anddried in an oven under reduced pressure. This resulted in 2.139 g (62%)of methyl 3-[(3-aminoquinolin-4-yl)carbamoyl]propanoate as a whitesolid.

LC-MS-PH-IFM-2-022-5: (ES, m/z): [M+H]⁺=274.1

2. Synthesis of N-(3-aminoquinolin-4-yl)-4-hydrozybutanamide

Into a 100-mL round-bottom flask, was placed a solution of methyl3-[(3-aminoquinolin-4-yl)carbamoyl]propanoate (2.139 g, 7.83 mmol, 1.00equiv) in tetrahydrofuran (50 mL). To the solution was added LiBH₄ (259mg, 11.75 mmol, 1.50 equiv). The resulting solution was stirred for 3 hat room temperature. The reaction was then quenched by the addition ofbrine. The resulting solution was extracted with dichloromethane and thecombined organic layers were concentrated under vacuum. The residue wasloaded on a silica gel column with dichloromethane/methanol (30:1) andchromatographed. This resulted in 1.674 g (87%) ofN-(3-aminoquinolin-4-yl)-4-hydroxybutanamide as a light yellow solid.

LC-MS-PH-IFM-2-022-7: (ES, m/z): [M+H]⁺=246.1

3. Synthesis of 3-[1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol

Into a 100-mL round-bottom flask, was placed a solution ofN-(3-aminoquinolin-4-yl)-4-hydroxybutanamide (1.674 g, 6.82 mmol, 1.00equiv) in ethanol/H₂O (55 mL, 10:1). To the solution was added NaOH(2.733 g, 68.33 mmol, 10.00 equiv). The resulting solution was stirredovernight at 80° C. in an oil bath. The resulting solution wasconcentrated under vacuum and the residue was loaded on a silica gelcolumn with dichloromethane/methanol (30:1) and chromatographed. Thisresulted in 935 mg (60%) of3-[1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol as a light yellow solid.

LC-MS-PH-IFM-2-022-11: (ES, m/z): [M+H]⁺=228.1

4. Synthesis of2-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate

Into a 50-mL round-bottom flask, was placed a solution of3-[1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol (340 g, 1.50 mol, 1.00equiv) in dichloromethane (5 mL). To the solution were added H₂O₂ (5 mL)and CH₃ReO₃ (50 mg, 0.20 mmol). The resulting solution was stirred for 1h at room temperature. The reaction was then quenched by the addition ofaqueous sodium bicarbonate. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (20:1) and chromatographed. This resulted in300 mg of 2-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate asa light yellow solid.

LC-MS-PH-IFM-2-022-12: (ES, m/z): [M+H]⁺=244.1

5. Synthesis of 3-[4-amino-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol(Compound 101)

Into a 50-mL round-bottom flask, was placed a solution of2-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate (666 mg,2.74 mmol, 1.00 equiv) in dichloromethane (8 mL). To the solution wereadded TsCl (781 mg, 4.11 mmol, 1.50 equiv) and NH₃H₂O (8 mL). Theresulting solution was stirred for 1 day at room temperature. Afterremoving the solvent, the crude product was purified by preparative HPLCwith the following conditions (Prep_HPLC_17): Column, X Bridge C18 OBDPrep Column, 10 μm, 19 mm×250 mm; mobile phase, Water (10 MMOL/LNH₄HCO₃) and ACN (8.0% ACN up to 16.0% in 15 min); Detector, UV 254/220nm. This resulted in 103.7 mg (16%) of3-[4-amino-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol as a white solid.

LC-MS-PH-IFM-2-022-0: (ES, m/z): [M+H]⁺=243.1

H-NMR-PH-IFM-2-022-0: (CD₃OD, 300 MHz, ppm): δ 7.98-7.95 (m, 1H),7.63-7.60 (m, 1H), 7.47-7.41 (m, 1H), 7.30-7.25 (m, 1H), 3.67-3.61 (m,2H), 3.06-2.96 (m, 2H), 2.12-2.01 (m, 2H).

Preparative Example 2—Compound 102

1. Synthesis of Methyl4-[[7-bromo-3-(3-[[(tert-butoxy)carbonyl](methyl)amino]propanamido)quinolin-4-yl]amino]butanoate

Into a 100-mL round-bottom flask, was placed a solution of methyl4-[(3-amino-7-bromoquinolin-4-yl)amino]butanoate (900 mg, 2.66 mmol,1.00 equiv) in dichloromethane (50 mL). To the solution were added3-[[(tert-butoxy)carbonyl](methyl)amino]propanoic acid (650 mg, 3.20mmol, 1.20 equiv), HATU (3 g, 7.89 mmol, 3.00 equiv) and DIEA (1.7 g,13.15 mmol, 5.00 equiv). The resulting solution was stirred overnight atroom temperature. The resulting solution was diluted with H₂O. Theresulting solution was extracted with of dichloromethane and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by preparative TLC(dichloromethane/MeOH=10:1). This resulted in 620 mg (crude) of methyl4-[[7-bromo-3-(3-[[(tert-butoxy)carbonyl](methyl)amino]propanamido)quinolin-4-yl]amino]butanoateas a yellow solid.

LC-MS-PH-IFM-7-106-5: (ES, m/z): [M+H]⁺=523.4

2. Synthesis of Methyl4-[7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate

Into a 25-mL round-bottom flask, was placed a solution of methyl4-[[7-bromo-3-(3-[[(tert-butoxy)carbonyl](methyl)amino]propanamido)quinolin-4-yl]amino]butanoate(350 mg, 0.67 mmol, 1.00 equiv) in methanol (6 mL). To the solution wasadded DIEA (3 mL). The resulting solution was stirred overnight at 80°C. The resulting mixture was concentrated under vacuum. The residue waspurified by Prep-TLC (dichloromethane/MeOH=10:1). This resulted in 170mg (50%) of methyl4-[7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoateas a yellow solid.

LC-MS-PH-IFM-7-106-6: (ES, m/z): [M+H]⁺=505.4

3. Synthesis of7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1-(4-methoxy-4-oxobutyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate

Into a 50-mL round-bottom flask, was placed a solution of methyl4-[7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate(170 mg, 0.34 mmol, 1.00 equiv) in dichloromethane (25 mL). To thesolution was added m-CPBA (125 mg, 1.50 equiv). The resulting solutionwas stirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by preparative TLC(dichloromethane/MeOH=10:1). This resulted in 120 mg (68%) of7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1-(4-methoxy-4-oxobutyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olateas a yellow solid.

LC-MS-PH-IFM-7-106-7: (ES, m/z): [M+H]⁺=521.2

4. Synthesis of Methyl4-[4-amino-7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate

Into a 50-mL round-bottom flask, was placed a solution of7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1-(4-methoxy-4-oxobutyl)-1H-imidazo[4,5-c]quinolin-5-ium-5-olate(120 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (10 mL). To thesolution was added TsCl (66 mg, 0.35 mmol, 1.50 equiv) and NH₄OH (3 mL).The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by preparative TLC (dichloromethane/MeOH=6:1). This resulted in100 mg of methyl4-[4-amino-7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoateas a yellow solid.

LC-MS-PH-IFM-7-106-8: (ES, m/z): [M+H]⁺=520.2

5. Synthesis of Methyl4-[4-amino-7-bromo-2-[2-(methylamino)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl]butanoate(Compound 102)

Into a 25-mL round-bottom flask, was placed a solution of methyl4-[4-amino-7-bromo-2-(2-[[(tert-butoxy)carbonyl](methyl)amino]ethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate(100 mg, 0.19 mmol, 1.00 equiv) in 4N hydrogen chloride/1,4-dioxane (10mL). The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by preparative HPLC with the following conditions: Column: XBridge Prep C18 OBD, 19*150 mm 5 um C-0013; Mobile phase: Phase A: Water(10 MMOL/L NH₄HCO₃), Phase B: CAN (20% B to 45% B in 9 min). Thisresulted in 33.8 mg (42%) of methyl4-[4-amino-7-bromo-2-[2-(methylamino)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl]butanoateas a white solid.

LC-MS-PH-IFM-7-106-0: (ES, m/z): [M+H]⁺=422.1

H-NMR-PH-IFM-7-106-0: ¹H NMR (300 MHz, DMSO-d₆): δ 8.08 (d, J=9.0 Hz,1H), 7.73 (d, J=2.4 Hz, 1H), 7.37-7.33 (m, 1H), 6.75 (s, 2H), 4.55-4.50(m, 2H), 3.66 (s, 3H), 3.04 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H),2.58-2.54 (m, 2H), 2.34 (s, 3H), 2.09-2.02 (m, 2H).

Preparative Example 3: General Procedure for Synthesis of7-Bromo-N⁴-(4-methoxybenzyl)quinoline-3,4-diamine

1. Preparation of 7-bromo-3-nitroquinolin-4-ol (400)

7-bromoquinolin-4-ol (4.5 g, 20.0 mol) was dissolved in propionic acid(34 mL). The mixture was heated to 130° C., and nitric acid (1.7 mL,70%) was added. The reaction was heated at 130° C. (bath temperature)for 4 hours at which time it was cooled to room temperature andfiltered. The resulting solid was washed with water (3×20 mL),2-propanol (20 mL), and hexanes (20 mL). The product was then driedunder high vacuum to provide 3.8 g (70.6%) of7-bromo-3-nitroquinolin-4-ol (400) as a tan powder and used in the nextstep without further purification. (ES, m/z): [M+H]⁺=269.2/271.3.

2. Preparation of 7-bromo-4-chloro-3-nitroquinoline (401)

7-Bromo-3-nitroquinolin-4-ol (400, 3.8 g, 14.12 mmol) was suspended inPOCl₃ (20 mL). Anhydrous DMF (1 mL) was added. The mixture was thenheated to 120° C. under an atmosphere of nitrogen for 3 hours at whichtime the reaction was cooled to room temperature. The precipitate wascollected by filtration, washed with water, and then partitioned betweenCH₂Cl₂ (60 mL) and a saturated aqueous solution of Na₂CO₃. The organiclayer was separated, washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford 3.3 g (11.5 mmol, 81%) of7-bromo-4-chloro-3-nitroquinoline (401) as a beige-colored solid. (ES,m/z): [M+H]⁺=287.1/288.9.

Note: It was discovered that if higher temperatures and longer reactiontimes are used, a significant amount of Cl—Br exchange occurs whichaffords an intermediate that does not undergo subsequent cross-couplingreactions.

3. Preparation of 7-bromo-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine(402)

7-bromo-4-chloro-3-nitroquinoline (401, 1.9 g, 6.62 mmol) was dissolvedin CH₂Cl₂ (20 mL). 4-methoxy benzylamine (0.85 mL, 6.7 mmol) was added,followed by NEt₃ (0.95 mL, 6.7 mmol). The mixture was stirred at roomtemperature for 4 h at which time it was diluted with CH₂Cl₂ (30 mL),washed with water, washed with brine, dried over Na₂SO₄, and filtered.The resulting solution was evaporated to dryness to afford(7-bromo-3-nitro-quinolin-4-yl)-(4-methoxy-benzyl)-amine (402) as ayellow foam (2.5 g, 6.44 mmol, 97%). This material was used in the nextstep without further purification. (ES, m/z): [M+H]⁺=388.3/390.1.

4. Preparation of 7-bromo-N⁴-(4-methoxybenzyl)quinoline-3,4-diamine(403)

(7-Bromo-3-nitro-quinolin-4-yl)-(4-methoxy-benzyl)-amine (402, 2.5 g,6.44 mmol) was dissolved in ethanol (60 mL) at room temperature. Tin(II) chloride hydrate (4.8 g, 21.2 mmol) was added in one portion. Themixture was stirred at 65° C. for 3 h at which time water (50 mL) wasadded, followed by a saturated aqueous solution of NaHCO₃ to pH ˜9. Themixture was extracted with EtOAc (3×60 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to afford7-bromo-N⁴-(4-methoxy-benzyl)-quinoline-3,4-diamine (403, 1.5 g, 4.2mmol, 65%). This material was used in the next step without furtherpurification. (ES, m/z): [M+H]⁺=357.9/360.1

Preparative Example 4: Example Preparation Method of Analogs WhereinR²=Hydroxyalkylene and R³=Aryl, Heteroaryl, Heterocyclyl, or Amino

1. Preparation of2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolone

To a solution of 7-bromo-N⁴-(4-methoxy-benzyl)-quinoline-3, 4-diamine(403, 1 g, 2.8 mmol) and 4-benzyloxy-butyric acid (0.5 mL, 2.82 mmol))in CH₂Cl₂ (10 mL) was added HATU (1.2 g, 3.15 mmol) and NEt₃ (1 mL, 7.17mmol). The mixture was stirred at room temperature for 12 hours at whichtime it was concentrated to remove all volatiles. EtOH (10 mL) wasadded, followed by NEt₃ (3 mL). The mixture was stirred in a 70° C. oilbath for 15 hours at which time it was cooled to room temperature. Mostvolatiles were evaporated in vacuo and the residue was partitionedbetween CH₂Cl₂ (30 mL) and water (30 mL). The CH₂Cl₂ layer was furtherwashed with water (30 mL), washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude2-(3-benzyloxy-propyl)-7-bromo-1-(4-methoxy-benzyl)-1H-imidazo[4,5-c]quinoline(1.2 g, 2.3 mmol, 80%) was used in the next step without furtherpurification. (ES, m/z): [M+H]⁺=516.4/518.1.

2. Preparation of2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline5-oxide

To a solution of2-(3-benzyloxy-propyl)-7-bromo-1-(4-methoxy-benzyl)-1H-imidazo-[4,5-c]quinoline(xx, 1.2 g, 2.3 mmol) in CH₂Cl₂ (15 mL) were added H₂O₂ (6 mL) andm-chloroperoxybenzoic acid (70% grade, 573 mg, 0.23 mmol, 0.10 equiv).The mixture was stirred for 14 hours at room temperature at which timeit was diluted with a saturated aqueous solution of NaHCO₃ and extractedwith CH₂Cl₂ (3×20 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give crude2-(3-benzyloxy-propyl)-7-bromo-1-(4-methoxy-benzyl)-1H-imidazo[4,5-c]quinoline5-oxide (1.1 g, 2 mmol, 89%) as a yellowish foam. (ES, m/z):[M+H]⁺=532.1/534.3

3. Preparation of2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine

To a solution of2-(3-benzyloxy-propyl)-7-bromo-1-(4-methoxy-benzyl)-1H-imidazo-[4,5-c]quinolone-5-oxide(1.1 g, 2 mmol) and NH₄OH (25 mL) in dichloromethane (25 mL) cooled in aice water bath, was added p-toluenesulfonyl chloride (850 mg, 4.45 mmol)in CH₂Cl₂ (5 mL) dropwise. The resulting solution was stirred another 30min after addition was complete. Water (20 mL) was added and the layerswere separated. The aqueous layer was extracted one more time withCH₂Cl₂ (30 mL). The combined organic layers were filtered through a padof Na₂SO₄ and the filtrate was concentrated in vacuo. The residue wastriturated with EtOAc/hexanes (1/3) and dried under high vacuum toafford2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amineas a yellow solid (880 mg, 1.64 mmol, 82%). (ES, m/z):[M+H]⁺=516.4/518.1.

4. Coupling with Aryl Bromide

a. General Procedure for Suzuki Coupling of Arylboronic Acids and Esters

To a solution of1-(4-methoxybenzyl)-2-(3-(benzyloxy)propyl)-7-bromo-1H-imidazo[4,5-c]quinolin-4-amine(40 mg, 75 μmol) was added an aryl(heteroaryl)boronic acid (orarylboronate ester) (2 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (5 mg), and an aqueoussolution of K₂CO₃ (1 mL, 2M aqueous) sequentially. The mixture washeated in a Biotage Initiator microwave reactor at 120° C. for 10 min.The organic layer was diluted with EtOAc and separated, and the aqueouslayer was extracted with EtOAc. The combined organic phases werefiltered and evaporated, and the crude residue used in the deprotectionstep without further purification.

b. Alternative Procedure: Ullman Coupling of N-Heterocycles, Lactams,and Amines

To a solution of2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine(25 mg, 47 μmol) in dry DMSO (2 mL) was added the N-heterocycle (orlactam or amine) (2 equiv), CuI (25 mg, 2 equiv), and Na₂CO₃ (30 mg, 4equiv) in sequence. The mixture was degassed with argon andN,N′-dimethyl-ethylenediamine (20 mg, 3 equiv) was added. The resultingmixture was stirred at 120° C. for 2 hours. The cooled mixture wasdiluted with EtOAc, filtered, and the solvent evaporated in vacuo. Thecrude residue was used in the deprotection step without furtherpurification.

c. Alternative Procedure: Stile Coupling of Stannanes

To a solution of2-(3-(benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine(25 mg, 47 μmol) and the aryl(heteroaryl)stannane (2 equiv) in dry1,4-dioxane (2 mL) was added PdCl₂(PPh₃)₂ (5 mg). The resulting mixturewas purged with nitrogen and stirred at 110° C. overnight. The cooledreaction mixture was diluted with EtOAc, the solution filtered, and thesolvents evaporated in vacuo. The residue was used in the deprotectionstep without further purification.

5. General Deprotection/Partial Deprotection Procedure

The crude product from the previous step was dissolved in TFA (2 mL) andstirred at 70° C. for approximately 3 hours while following the progressof the reaction by LC/MS. Once the PMB protecting group was completelycleaved and the benzyl was cleaved to the extent of approximately 50% asindicated by LC/MS (note: the incipient primary alcohol appeared as thetrifluoroacetate), the mixture was evaporated. The resulting residue wasdissolved in MeOH and treated with an aqueous 2M solution of NaOH toobtain a mixture of free alcohol and benzyl ether products. Acetic acidwas added to neutralize the mixture, which was then evaporated andpurified by HPLC to separate the alcohol and benzyl ether as theirrespective hydrochloride salts. Alternatively, the TFA solution abovewas heated at 70° C. until the benzyl group was completely cleaved tofurnish the completely deprotected alcohol.

The compounds depicted in Table 3 were made according to the abovesynthetic procedures.

TABLE 3 LCMS Structure Compound IUPAC NAME [M + H]+

144 7-phenyl-2-(3- phenylmethoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine 409.2

145 3-(4-amino-7-phenyl-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol319.1

146 2-(3-phenylmethoxypropyl)-7- pyridin-3-yl-1H-imidazo[4,5-c]quinolin-4-amine 410.2

147 3-(4-amino-7-pyridin-3-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 320.1

148 2-(3-phenylmethoxypropyl)-7- pyridin-4-yl-1H-imidazo[4,5-c]quinolin-4-amine 410.2

149 3-(4-amino-7-pyridin-4-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 320.1

150 7-(2,5-dimethylpyrazol-3-yl)-2- (3-phenylmethoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine 427.2

151 3-[4-amino-7-(2,5- dimethylpyrazol-3-yl)-1H-imidazo[4,5-c]quinolin-2- yl]propan-1-ol 337.2

152 2-(3-phenylmethoxypropyl)-7- (1-propylpyrazol-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine 441.2

153 3-[4-amino-7-(1-propylpyrazol- 4-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 351.2

154 7-(2-methylpyrimidin-5-yl)-2- (3-phenylmethoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine 425.2

155 3-[4-amino-7-(2- methylpyrimidin-5-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 335.1

156 3-[4-amino-7-[2- (dimethylamino)pyrimidin-5-yl]-1H-imidazo[4,5-c]quinolin- 2-yl]propan-1-ol 364.2

157 7-(2-fluoropyridin-3-yl)-2-(3- phenylmethoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine 428.2

158 3-[4-amino-7-(2-fluoropyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 338.1

159 3-(4-amino-7-propan-2-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 285.2

160 3-(4-amino-7-propyl-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol285.2

161 3-(4-amino-7-cyclopentyl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 311.2

162 3-(4-amino-7-ethyl-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol271.1

163 3-(4-amino-7-phenoxy-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol335.1

164 3-[4-amino-7-(2- methylimidazol-1-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 323.1

165 3-(4-amino-7-chloro-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol277.1

166 3-(4-amino-7-pyrrolidin-1-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 312.2

167 3-(4-amino-7-piperidin-1-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 326.2

168 3-(4-amino-7-morpholin-4-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 328.2

170 3-[4-amino-7-(6-aminopyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 335.1

171 3-[4-amino-7-(4- methoxypyridin-3-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 350.1

172 3-[4-amino-7-(6-methylpyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 334.1

173 3-[4-amino-7-(6- methylsulfanylpyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2- yl]propan-1-ol 366.1

174 3-(4-amino-7-cyclohexyl-1H- imidazo[4,5-c]quinolin-2- yl)propan-1-ol325.2

175 3-[4-amino-7-(5- methoxypyridin-3-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 350.1

176 5-[4-amino-2-(3- hydroxypropyl)-1H- imidazo[4,5-c]quinolin-7-yl]pyridin-2-ol 336.1

177 3-[4-amino-7-[2- (dimethylamino)-1,3-thiazol-4-yl]-1H-imidazo[4,5-c]quinolin- 2-yl]propan-1-ol 369.1

178 3-(4-amino-7-pyrazol-1-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 309.1

179 3-(4-amino-7-imidazol-1-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 309.1

180 N-[4-amino-2-(3- hydroxypropyl)-1H- imidazo[4,5-c]quinolin-7-yl]benzamide 362.1

181 3-[4-amino-7-(4- methylpyrazol-1-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 323.1

182 3-[4-amino-7-(benzimidazol-1- yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 359.1

183 1-[4-amino-2-(3- hydroxypropyl)-1H- imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one 326.1

184 3-[4-amino-7-(1,3-thiazol-2-yl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 326.1

185 3-(4-amino-7-pyridin-2-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 320.1

186 3-(4-amino-7-thiophen-3-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 325.1

187 3-(4-amino-7-thiophen-2-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 325.1

188 3-(4-amino-7-pyrimidin-5-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 321.1

189 3-[4-amino-7-(1H-pyrazol-3- yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 309.1

190 3-[4-amino-7-(2- methylpyrazol-3-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 323.1

191 3-(4-amino-7-quinolin-3-yl-1H- imidazo[4,5-c]quinolin-2-yl)propan-1-ol 370.1

192 3-(4-amino-7-isoquinolin-4-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 370.1

193 3-[4-amino-7-(1- methylpyrazol-4-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 323.1

194 3-[4-amino-7-(3,5- dimethylpyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-2- yl]propan-1-ol 337.2

195 3-[4-amino-7-(1,2-oxazol-4-yl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 310.1

196 3-[4-amino-7-(oxan-4-yl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 327.2

197 3-(4-amino-7-pyrrolidin-3-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 312.2

198 3-(4-amino-7-piperidin-4-yl- 1H-imidazo[4,5-c]quinolin-2-yl)propan-1-ol 326.2

199 3-[4-amino-7-(2- methylphenyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 333.2

200 3-[4-amino-7-(2-chlorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 353.1

201 3-[4-amino-7-(2- methoxyphenyl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 349.1

202 2-[4-amino-2-(3- hydroxypropyl)-1H- imidazo[4,5-c]quinolin-7-yl]benzonitrile 344.1

203 3-[4-amino-7-(2-fluorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 337.1

204 3-[4-amino-7-(3-chlorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 353.1

205 3-[4-amino-7-(3- methylphenyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 333.2

206 3-[4-amino-7-(3- methoxyphenyl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 349.1

207 3-[4-amino-2-(3- hydroxypropyl)-1H- imidazo[4,5-c]quinolin-7-yl]benzonitrile 344.1

208 3-[4-amino-7-(3-fluorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 337.1

209 3-[4-amino-7-(4-chlorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 353.1

210 3-[4-amino-7-(4- methylphenyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 333.2

211 3-[4-amino-7-(4- methoxyphenyl)-1H- imidazo[4,5-c]quinolin-2-yl]propan-1-ol 349.1

212 3-[4-amino-7-(4-fluorophenyl)- 1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 337.1

213 3-[4-amino-7-(4-methylpyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 334.1

214 3-[4-amino-7-(2-methylpyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 334.1

215 3-[4-amino-7-(2-chloropyridin- 3-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-1-ol 354.1

Example 4: Bioassay

Inhibition of IL-1β Production in PMA-Differentiated THP-1 Cells

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in RPMI 1640 containing 10% heatinactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml),and maintained in log phase prior to experimental setup. Prior to theexperiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate)(10 μg/ml) for 24 hours. The day of the experiment the media was removedand attaching cells were treated with trypsin for 2 minutes, cells werethen collected, washed with PBS (phosphate buffer saline), spin down,resuspended in 2% heat inactivated FBS with RPMI at a concentration of1×106 cells/ml, and 100 μl was plated in a 96 well plate. Cells wereincubated with compounds for 4 hours. Cell free supernatant wascollected and the production of IL-1β was evaluated by ELISA. Compoundswere dissolved in dimethyl sulfoxide (DMSO) and added to the culturemedium to achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or0.1 μM). A vehicle only control was run concurrently with eachexperiment. Final DMSO concentration was 1%. Compounds exhibit adose-related increase of IL-1β production in PMA-differentiated THP-1cells.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound or salt as claimed in claim 1 and oneor more pharmaceutically acceptable excipients.
 3. A method of treatingmelanoma or basal cell carcinoma, comprising administering to a subjectin need of such treatment an effective amount of a compound as claimedin claim
 1. 4. The method of claim 3, wherein the compound isadministered in combination with one or more additional cancertherapies.
 5. The method of claim 4, wherein the one or more additionalcancer therapies comprises surgery, radiotherapy, chemotherapy, toxintherapy, immunotherapy, cryotherapy or gene therapy, or a combinationthereof.